It is important for clinicians to be informed of a patient's inappropriate use of prescribed/nonprescribed medications and/or illicit drugs to be able to properly manage their patient's care. As such, strict adherence to pharmacological dosage regimens is a prerequisite to the success of most treatments, particularly in patients in drug abuse programs or chronic pain programs. Although drug screening specimen collection procedures have been used to ensure specimen integrity, patients demonstrate considerable ingenuity in their efforts to defeat the testing process (1-4). Methods used by patients for avoiding drug misuse detection have included: diversion, excessive water consumption, ingestion of diuretics (e.g., herbal teas) and urine substitution. Individuals who divert pain medication will often “hold” a few pills to be taken before a physician visit (the “white lab coat” effect). This allows the medication to show up in their system in order to ensure that the physician renews the prescription, thereby allowing them to continue diverting the medication.
Individuals will also overuse medications, often gaining it from multiple sources. These individuals often pass the basic screening tests performed at a clinic and continue to receive the medication. Furthermore, patients treated with narcotics for the management of chronic pain also have been documented to under report their use of medications, especially for the opioid class of medications (5-11). Thus, to properly manage patient care, clinicians use external sources of information such as interviews with spouses, review of medical records, input from prescription monitoring programs, and testing of biological samples (e.g., urine) to detect inappropriate use of prescribed and nonprescribed medications, as well as, illicit drugs.
It has been previously reported that urine testing has the greatest potential for determining true compliance (12). The major problem facing urine testing is the large amount of variance in urine drug concentrations, mostly due to variations in hydration and urinary output volume (44, 45, 34). In a well-hydrated person, the level of drug metabolites per milliliter may be quite small, while a poorly hydrated person will show significantly higher levels of metabolites per milliliter. Studies have reported that if hydration is controlled, the drug metabolite level will be more consistent and accurate for urine testing. It has also been suggested that creatinine normalization may be used in correcting for variations in metabolite urine tests (13, 17, 35, 36, 34, 40, 42, 44, 46); however, others have been skeptical of this practice (41, 45).
Creatinine is a metabolite of creatine, and is an end-product of muscle metabolism excreted in the urine. Creatinine formation and excretion are directly proportional to total muscle mass and are roughly proportional to body weight. Creatinine is excreted in relatively constant amounts of 1.0 to 2.5 g/day regardless of urinary volume (14, 15). Also normalization of the excretion of a drug to the creatinine concentration reduces the variability of analyte measurement attributed to urine dilution.
Use of creatinine to reduce variance due to dilution has been suggested in the literature. However, most of these reports focus on illicit drug abuse where the concept of dose-specific use of the urine screening does not apply due to non-uniform doses and delivery systems of the illicit drugs being studied, i.e., cocaine and marijuana (16) or have not attempted to develop a normative database with confidence intervals or regression models (42). Literature in this field has also pointed to the use of urine creatinine as one method for possible adjustment that could be made in, for example, a one-step dilution protocol, but which may produce spurious results when urine creatinine is either extremely high or low (17).
Few, however, have attempted to employ use creatinine to adjust for hydration in order to monitor how a prescription drug is being used. Manno et al., reported that the Syva EMIT®-d.a.u. urine cannabinoid assay (Dade Behring, Palo Alto, Calif.) could be successfully used for detecting marijuana use patterns in a urine surveillance program if creatinine was used to reduce variance due to hydration (26). It was also reported that a delta-9-tetrahydrocannabinol-9-carboxylic acid (THCA)/creatinine ratio should decrease over time when there is no new use and a recommendation was made that when comparing results, the THCA/creatinine ratio should decrease by 50% every 2-10 days depending on the individual. More recently studies have confirmed the usefulness of the THCA/creatinine ratio under controlled-dosing conditions with marijuana smokers (37, 38). For example, it is believed that sequential creatinine normalized urine drug concentrations could predict whether marijuana exposure had re-occurred or if the presence of THCA in urine was due to continued clearance from the body in 85% of the cases. Reports have also shown that ratios in a light or infrequent user can decrease faster than in a heavy or frequent user. Some research has shown the value of using creatinine when looking at urine testing for cotinine and the effects of passive smoke inhalation (43); however, others have remained skeptical about this benefit (41).
Still other studies have attempted to develop a urine drug screen protocol by performing dose specific analyses that identified possible improper users, but have downplayed the importance of those findings (42). In these studies, the addition of a ratio of EDDP metabolite to methadone dose and then dividing that by the urine creatinine (i.e., [EDDP/methadone dose]/urine creatinine) may have disrupted the analysis and lessened the overall value of the correction. Urine creatinine has been recommended for use in the fields of illicit drug use (e.g., cocaine, marijuana, etc.). However, it has never been used to develop dose-specific confidence intervals or regression analyses that would allow clinicians to verify patient medication use that is consistent with proper use of the prescription through urine testing, with the exception of the above noted study that had the described flaws. To date no researchers have attempted to develop a urine drug screen protocol for abusable prescription medications that would enable dose specific testing and allow identification of proper vs. improper use of the medication in question. Rather, to date, a test result is purely negative or positive as to the presence or absence of a drug metabolite in the urine. Accordingly, it would be useful to develop a method to assess with confidence patient adherence to prescribed drug treatment regimens.